Liver diseases include toxic hepatitis such as alcoholic hepatitis and cirrhosis, hepatitis C, which is the most common viral hepatitis, and less commonly the immunological liver diseases characterised by chronic inflammation.
Therapeutic attempts to improve liver function have always been secondary to treatment of the primary disease processes, but there have been many attempts to improve function by targeting different components of the pathological processes. One key method employed has been the use of antioxidants beginning with the herbal extracts silymarin and silibinin (reviewed by Flora et al, 1998). However, the efficacy of silymarin has been disappointing in alcoholic liver disease (Angulo et al, 2000), and there is the potential for hepatotoxic effects (Bass; 1999). More recently, tocopherol, dipyridamole (Novikov et al, 1991; Vargas et al, 2001), and a range of modern, both synthetic and naturally-occurring, antioxidants have been used (Vaidya et al. 1996)
Included among these are the calcium blocking agents verapamil, diltiazem, and amlodipine (Mason et al, 1999), and also nitrendipine (Thurman and colleagues, 1998). At first, it was thought that these agents acted directly on liver cells to block calcium entry as they do in excitable tissues such as the myocardium and in arteries (Liang and Thurman, 1992), however, it was soon realised that the liver does not have voltage-gated calcium channels, which are the target of these drugs in excitable tissues. Therefore, if these drugs were acting on the liver, they needed to act in a different way. Thus, it was found that many calcium blockers were also powerful antioxidants (Heo et al, 1997).
It has also been proposed that calcium channel blockers may dilate the hepatic artery to increase delivery of oxygenated blood to the liver (McLean. 1998). However, the protective effect of drugs such as verapamil, diltiazem (Liang and Thurman, 1992; Romero and colleagues, 1994) and the other calcium blockers occurs in isolated cells. The effects on hepatic arterial blood flow of calcium blockers administered orally in low doses have not been confirmed. Diltiazem has also been shown to have no effect on microvascular blood flow within the liver (Marteau and colleagues, 1988).
Patents suffering hepatitis have an impaired ability to absorb thiamine and yet thiamine concentration in the blood is often difficult to measure. The production of energy in the mitochondria is thus severely compromised in cells of a diseased liver.
The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge as at the priority date of any of the claims.